The neuropathological features of schizophrenia remain elusive. Golgi studies reveal a lower density of dendritic spines, compared with nonpsychiatric subjects, in frontal cortex and subiculum. However, they do not afford sufficient resolution to ascertain whether spines are truly lost or rather abnormally small, and whether the visible spines are structurally normal. In vivo imaging studies, genetic associations, and biochemical studies suggest that myelin sheaths in the white matter might be abnormally thin or might contain foci of disruption;light microscopic studies of white matter have so far revealed little, and at best could show only indirect evidence of such abnormalities. These important issues in the morphology of schizophrenia can be best resolved by ultrastructural studies. We propose to establish an electron microscope (EM) facility in Macedonia, to train people to perform and interpret electron microscopy (particularly of the brain), and to have them start to work on these problems in schizophrenia. In particular, we propose quantitative measures of spine volumes and relative frequencies of morphological types of spines in frontal cortex and subiculum, and measures of axonal and myelin sheath diameters in optic nerve, corpus callosum, and cingulum bundle. A longstanding collaboration between the School of Medicine of the University }Ss. Cyril &Methodius} in Skopje, Republic of Macedonia, and the New York State Psychiatric Institute and Columbia University has produced an ongoing collection of autopsy brains from subjects with and without psychiatric illnesses. This collection, used for numerous funded studies in the US and Canada, will form the basis for the proposed study in Macedonia, supplying appropriate material from cases that are well- characterized clinically, neuropathologically, and toxicologically. A fully functional JEOL 100x12 electron microscope and all needed ancillary equipment have been shipped to Macedonia and await installation. An experienced electron microscopist will run the EM laboratory and will train people in its use. One such trainee will come to the United States for further training by experts in EM of the nervous system, and will then return to Macedonia for supervised completion of the studies. PUBLIC HEALTH RELEVANCE: Schizophrenia is a common disease that produces lifelong disability. In contrast to many other brain diseases, the critical structural changes in the brain have not been definitively identified. Indirect evidence suggests that structural changes are likely to be localized in dendritic spines and myelin sheaths, brain structures whose details can be visualized only by electron microscopy. We propose to establish an electron microscope facility in Macedonia, where we will collect autopsy brains and examine them to see if these abnormalities are present. Conclusive and detailed knowledge of the structural abnormalities of the brain are crucial too understanding the cause of the illness and to finding effective treatments or cures.